An NIDDK K23 Mentored Patient-Oriented Research Career Development Award is requested to provide support for Gregory S. Sayuk, MD, MPH to continue a rigorous program of mentored methodologic training and investigation into the pathophysiologic role of the central nervous system in irritable bowel syndrome (IBS). IBS is a common abdominal pain disorder, affecting up to one in five individuals. Our limited appreciation for the mechanisms underlying IBS has resulted in a lack of targeted IBS therapies. Though in the past, studies evaluating the mechanistic basis of IBS have focused on bowel-specific factors, more recently evidence has emerged to suggest a potential role of abnormal brain responses to peripheral pain signals in the development of IBS. Of particular interest to the investigator is the overlap of IBS with somatization, a condition characterized by multiple unexplained pain comorbidities. Present in one-third of IBS subjects, somatization results in poor IBS clinical outcomes. The overall goals of the applicant's research are: (1) to elucidate the mechanisms by which somatization influences brain responses to peripheral pain signals in IBS, and (2) to determine whether these differences in CNS responses based on the presence of somatization are relevant to IBS symptom experiences. The proposed investigations are a logical extension of the preliminary data which provided initial evidence of a unique IBS-somatization pattern of brain activations within the homeostatic afferent processing network (HAPN), a group of brain regions important to the affective and cognitive response to pain. The proposed research will examine the response of these same brain regions to more generalized stimuli (somatic and visceral), and then assess the influence of centrally-acting IBS therapies on these brain regions. The overarching hypothesis of this research is that abnormal HAPN responses to visceral stimuli have mechanistic relevance in IBS, particularly in the subset with comorbid somatization (IBS- S+). A series of relevant, multidisciplinary mentorship and career development activities also are described, including additional training in neuroanatomy and functional neuroimaging, as building blocks for a career as an independent investigator IBS neuropathophysiology. PUBLIC HEALTH RELEVANCE: This study will examine brain responses to bowel pain signals in irritable bowel syndrome (IBS). It is hypothesized that in a portion of IBS subjects, particularly those with multiple pain syndromes ("somatization"), abnormal brain interpretation of bowel signals may be responsible for the pain of IBS, and moreover may affect patient responses to proven treatments.